Although chemoradiation for patients with locally advanced head and neck cancer improves survival compared to radiation alone, combination treatment is associated with an increased rate of serious and life threatening mucositis and dysphagia. EGFR plays a key role in head and neck cancer, in that its over-expression is associated with more aggressive behavior, and its blockade increases the survival of patients treated with radiation without increasing (non-skin) toxicity. In addition, we have carried out preclinical studies indicating that a decrease in activation of key signal transduction molecules after cetuximab administration may predict the response to the combination of cetuximab and radiation. The goal of this application is to determine the pharmacodynamic profile of response in patients receiving cetuximab and radiation so that we can determine who benefits from this extremely expensive and moderately toxic therapy. We wish to identify in patients the established preclinical and novel downstream markers of EGFR activity that are associated with EGFR inhibition and eventual response. We also propose preclinical studies to optimize the use of cetuximab in combination with chemotherapy that will be incorporated into future clinical trials. These goals will be achieved through 3 specific aims: Specific Aim 1 is to improve the outcome of patients with locally advanced head and neck squamous cell carcinoma who would not be anticipated to benefit from adding chemotherapy to radiation, and who would typically receive radiation alone, by using cetuximab-radiation. Specific Aim 2 is to discover potential new biomarkers (Aim 2A) and to validate in preclinical models the potential of new and established markers (Aim 2B) of EGFR activity to predict response to cetuximab (with radiation). Specific Aim 3 is to carry out preclinical studies to determine the optimum schedule for combining EGFR inhibition with chemoradiotherapy, with the goal of designing a future clinical trial for patients who are candidates for chemotherapy.